General mechanisms of neurotoxicity have been studied with two compound types-the parkinsonian syndrome producing 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and its analogues, and the uncommon plant amino acid 2-amino-3-(methylamino)-propanoic acid (BMAA), a putative neurotoxin associated with Guamanian amyotrophic lateral sclerosis/parkinsonism dementia (ALS/PD). The characterization of the toxicity produced by 4'- amino MPTP has shown striatal dopamine depletion in mice and dogs similar to the specific lesions produced by MPTP. A dose-response study in dogs has shown that prolonged alterations in striatal dopamine metabolism result from sub-toxic doses of these neurotoxins, and that the degree of monoamine oxidase (MAO) inhibition is correlated to the high concentrations of the pyridinium metabolites which persist for weeks. It is suggested that presynaptic sequestration and retention of the pyridinium metabolites by strital dopaminergic terminals results in the MAO inhibition. The magnitude and duration of effects of a single infusion of MPTP or 4'-amino- MPTP was followed in the plasma of dogs for six weeks. The prolonged depression of deaminated metabolites was consistent with presynaptic inhibition of MAO within sympathetic terminals, which may be a useful indicator of exposure to MPTP-like neurotoxins. Mass spectrometric assay of BMAA has been used to determine its pharmacokinetics and blood-brain permeability in the rat. BMAA may reach the potentially toxic levels in the brain, but only after doses which exceed those possible from dietary cycad flour. The oral bioavailability of BMAA was determined in the primate using stable isotope labelled BMAA, and it was found that >80% was absorbed into systemic circulation. Thus, other routes of administration (i.e., poltices) are not likely to deliver significantly higher quantities of BMAA than those encountered from the diet. Oxidative damage to neuronal DNA has been implicated in the pathogenesis of neurodegenerative disorders, and to test this hypothesis gas chromatographic-mass spectrometric methods are being developed to quantify oxidized thymine as thymine glycol. Hydroysis and borohydride reduction of DNA releases 2-methylglyceric acid, which is derivatized for analysis. Preliminary results suggest that this assay will be applicable to DNA isolated from human tissues.